In the era of target-based cancer therapies there is still missing a univocal hit for treating cancer metastatic spread, which is ultimately the main cause of cancer death. Non-protein-coding RNA transcripts (ncRNAs) were for long regarded as transcriptional noise; interestingly, it turns out that most of the genome does not carry protein-coding genes (PCGs) and yet is transcribed in a developmentally regulated manner producing ncRNAs with biologically relevant functions (e.g. development and tumor). As for tumor initiation, also for tumor metastasis, it is now becoming common knowledge that the set of metastasis promoting and suppressing genes consists both of PCGs and ncRNAs. Notwithstanding the growing interest in ncRNAs, the ability of forward genetic screens to discover novel genes has not been used in the ncRNA field. Therefore, with the present project we will develop a novel forward genetic screen that specifically retrieves ncRNAs. We will use this genetic screen in human intestinal epithelial cells, which will be tested in anoikis (death induced by anchorage absence) resistance assay. Cells that survive anoikis, which is a rate limiting step during cancer cell metastasis, will have loss of function mutations in ncRNA genes that we will then proceed to characterize.The present proposal is relevant for the 2011 People Work Programme since it will support the applicant Milena Sabrina Nicoloso in establishing an independent research position in Europe (as a group leader) and ultimately it will improve EU, Italy and the Host Institute excellence thanks to the knowledge and expertise that the applicant acquired during a 5 year international experience in EU competitor countries.